6-Fluoro-vitamin D3: A new antagonist of the biological actions of vitamin D3 and its metabolites which interacts with the intestinal receptor for 1α,25(OH)2-vitamin D3

Design and Synthesis of Fluoro Analogues of Vitamin D

“…In 1980, the first attempt to synthesize 19,19-difluorovitamin D 3 (46) starting from 19-oxocholesteryl acetate (47) via photoirradiation and thermal isomerization reactions using diene (48) failed, because the final thermal isomerization step by [1,7]-sigmatropic rearrangement did not proceed in the presence of the difluoromethyl group at the C10 position (Scheme 17) [41].…”

“…The biological profile of the analogue was evaluated in vivo, revealing that 54 had no biological effect on either intestinal calcium absorption or bone calcium mobilization. However, it significantly inhibited both VD3-and 1α,25(OH)2D3-mediated intestinal calcium absorption through a direct interaction with VDR [46]. Scheme 20.…”

Synthesis of schumanniophytine and isoschumanniophytine

“…The solid was suspended in petroleum ether and filtered to give 24 (41.8 g, 131 mmol, 98%) which was ordinarily used without further purification. Successive recrystallizations from ethanol, acetone/diethyl ether, and acetone gave 24 as yellow crystals: mp 128-130 °C (lit.9 mp 130-131 °C); NMR (CDC13) 2.34 (3 H, s), 2.42 (3 H, s), 2.44 (3 H, s), 2.55 (3 H, s), 6.84 (1 H, d, J = 2.2 Hz), 7.20 (1 H, d, J = 2.2 Hz); MS m/z (rel intensity) 319 (18), 318 (M\ 4), 227 (35), 276 (91), 234 (100); IR (CHCI3) v 1778,1687,1644,1623,1553,1427,1335 cm'1.…”

“…The mixture was evaporated to give a pale-purple solid residue. The residue was separated by preparative TLC (1000-µ plate, 5:1 ethyl acetate/diethyl ether) to give 14 (44 mg, 0.12 mmol, 86%) as a white solid: NMR (CDC13) 2.36 (3 H, d, J = 0.6 Hz), 3.90 (3 H, s), 5.29 (2 H, s), 6.04 (1 H, q, J = 0.6 Hz), 6.45 (1 H, s), 7.41 (5 H, m); MS m/z (rel intensity) 376 (5, M+), 374 (5, M+), 92 (8), 91 (100); IR (CHC13) v 1659,1630,1595,1391,1335 cm'1.…”

Synthesis and biological evaluation of 6-methyl analog of 1α,25-dihydroxyvitamin D3

“…Although more than 3000 different structural analogs of the natural hormone have been obtained and tested to date [7], very few of them were characterized by substitution of the intercyclic C(5) C(6)-C(7) C(8) diene moiety. 6-Fluorovitamin D 3 (3) was synthesized by Dauben et al [8] and this compound has been shown to antagonize the activity of 1␣,25-(OH) 2 D 3 , especially intestinal calcium absorption, in vivo in chicken [9]. The synthesis of 6-methylvitamin D 3 (4) Mazur [10] using a 6-oxo-3,5-cyclovitamin D precursor; the same compound was also obtained by Yamada et al [11] by reductive thermal desulfonylation of the 6-methylated vitamin D 3 -sulfur dioxide adduct.…”